Rifampicin Explorative PK Study for Tuberculous Meningitis Comparing Oral and Intravenous Preparation (REMOVER)

This study has been completed.
Sponsor:
Collaborator:
Radboud University
Information provided by (Responsible Party):
Universitas Padjadjaran
ClinicalTrials.gov Identifier:
NCT01802502
First received: February 27, 2013
Last updated: June 15, 2014
Last verified: June 2014
  Purpose

Tuberculous (TB) meningitis is the most severe manifestation of TB infection, leaving up to 50% of patients dead or neurologically disabled. Current treatment is similar to treatment of lung TB, although penetration of some antibiotics into the brain is poor and the immune-pathology of TB meningitis is very different from pulmonary TB. In a recent phase II clinical trial from the investigators group, the first of its kind globally, intensified antibiotic treatment, with moxifloxacin and high dose rifampicin, strongly reduced mortality of TB meningitis.

The investigators aim to examine the effect of intensified antibiotic treatment on mortality and morbidity of TB meningitis in a phase 3 clinical trial, preceded with an explorative pharmacokinetic (PK) study to examine if higher oral doses rifampicin result in exposures similar to the i.v. dose used in our phase 2 trial, since oral rifampicin could be implemented much easier in low-resource settings.


Condition Intervention Phase
Tuberculous Meningitis
Drug: Rifampicin intravenous
Drug: Oral rifampicin
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Bio-equivalence Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Explorative PK Study Comparing 600 mg Rifampicin i.v. With 750 mg and 900 mg Rifampicin Oral in Tuberculous Meningitis Patients

Resource links provided by NLM:


Further study details as provided by Universitas Padjadjaran:

Primary Outcome Measures:
  • Pharmacokinetic profile of several rifampicin dose [ Time Frame: Day 2 and Day 14; 6 time points for blood analysis, and 1 time point for CSF analysis ] [ Designated as safety issue: Yes ]
    We will measure plasma drug concentration at hour 0, 1, 2, 4, 8, and 12, while CSF drug concentration will be measured at a single time point i.e. at hour 3-6 post dose. The sampling days will be (1) within the first three days, and (2) at day 14 of the intensified treatment.


Secondary Outcome Measures:
  • mortality [ Time Frame: early (1 month) and late (6 months) ] [ Designated as safety issue: No ]
    We will measure early and late mortality


Enrollment: 30
Study Start Date: June 2013
Study Completion Date: April 2014
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Rifampicin 600 mg
Subjects in this arm receive 600 mg rifampicin intravenously
Drug: Rifampicin intravenous
Other Name: Rifadin
Experimental: rifampicin 750 mg
Subjects in this arm receive 750 mg rifampicin orally
Drug: Oral rifampicin
Other Name: Rifampisin (Kimia Farma, Bandung, Indonesia)
Experimental: rifampicin 900 mg
Subjects in this arm receive rifampicin 900 mg orally
Drug: Oral rifampicin
Other Name: Rifampisin (Kimia Farma, Bandung, Indonesia)

Detailed Description:

Introduction:

In a recent clinical trial the investigators have shown that a higher dose of rifampicin administered intravenously (600 mg iv) during the first 2 weeks of treatment is safe and associated with a survival benefit in adults with TB meningitis. An oral (rather than iv) dose would help implementation of intensified treatment for TB meningitis. However, it is hard to predict what oral dose of rifampicin will result in rifampicin exposures similar to 600 mg iv, due to differences in bio-availability (oral vs. iv) and the unpredictable dose-concentration relationship (nonlinear pharmacokinetics of rifampicin). Therefore the investigators aim to examine the pharmacokinetic of 2 higher doses of rifampicin (750 mg and 900 mg) given orally, and compare the pharmacokinetic profiles with the result of our previous study using 600 mg rifampicin iv.

General Objective:

To help establish the optimized treatment regimen for TB meningitis

Specific Objectives:

  1. To explore whether exposures resulting from oral rifampicin 750 mg or 900 mg are similar to exposures after intravenous rifampicin 600 mg during the first two days of treatment
  2. To explore whether exposures resulting from oral rifampicin 750 mg or 900 mg are similar to exposures after 14 days of treatment (stabilized rifampicin concentrations, i..e steady-state)
  3. To evaluate the safety and tolerability of high dose of oral rifampicin
  4. To evaluate neurological response and mortality after 2 weeks of treatment with high dose rifampicin

Study Design:

Explorative pharmacokinetic study; randomized, three-arm, two-period evaluation.

Study procedure:

After diagnosis of TB meningitis, eligible patients will be randomized to get either oral 750 mg, oral 900 mg, or iv 600 mg rifampicin for 14 days in combination with standard oral TB drugs (isoniazid 300 mg/day, ethambutol 750 mg/day, and pyrazinamide 1500mg/day) and adjuvant dexamethasone i.v. and pyridoxine.

Serial blood samples will be taken 6 times from 0, 1, 2, 4, 8, and 12 hour after drug administration at the first or second day of treatment and at day 14 (steady-state). Single cerebrospinal fluid (CSF) sample will be taken 3-6 hours after administration at the same day of blood sampling days.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 18 years or older
  • Probable/possible tuberculosis meningitis using uniform case definition
  • Agree to participate in the study

Exclusion Criteria:

  • Patient with antituberculosis treatment within last 2 weeks.
  • Increase liver function >5x upper limit of normal
  • Pregnancy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01802502

Locations
Indonesia
Hasan Sadikin Hospital
Bandung, West Java, Indonesia, 40122
Sponsors and Collaborators
Universitas Padjadjaran
Radboud University
Investigators
Principal Investigator: Rovina Ruslami, M.D., PhD Faculty of Medicine Universitas Padjadjaran - Dr. Hasan Sadikin Hospital Bandung
  More Information

Publications:
Responsible Party: Universitas Padjadjaran
ClinicalTrials.gov Identifier: NCT01802502     History of Changes
Other Study ID Numbers: TB-201302.01
Study First Received: February 27, 2013
Last Updated: June 15, 2014
Health Authority: Indonesia: National Agency of Drug and Food Control

Keywords provided by Universitas Padjadjaran:
tuberculous meningitis
rifampicin
bioequivalence
oral administration
intravenous administration

Additional relevant MeSH terms:
Meningitis
Meningitis, Bacterial
Tuberculosis
Tuberculosis, Meningeal
Actinomycetales Infections
Bacterial Infections
Central Nervous System Bacterial Infections
Central Nervous System Diseases
Central Nervous System Infections
Gram-Positive Bacterial Infections
Mycobacterium Infections
Nervous System Diseases
Tuberculosis, Central Nervous System
Rifampin
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antitubercular
Antitubercular Agents
Enzyme Inhibitors
Leprostatic Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 30, 2014